Combined Cancer Therapy with RF Ablation and Drug-Loaded Nanopreparations Our goal is to improve tumor destruction by rationally combining image-guided, minimally invasive imageguided radiofrequency (RF) thermal ablation with adjunctive nanotherapies. We propose to match the loaded agents within our nanopreparations to exploit key mechanisms generated by thermal ablation including cell stress and apoptosis, and more peripherally heat shock protein (HSP) production, as well as use nanodrug enhanced RF-induced hyperthermia to help overcome multidrug resistance. Accordingly, the current proposal will initially cover nanopreparations containing powerful proapoptotic agents such as paclitaxel (Aim 1), cell stress inducers such as GLA and BSO (Aim 2), and quercitin a known down-regulator of HSP (Aim 3). In general, we will adhere to a strategy that has proven successful for our translation of the paradigm of RF ablation combined with Doxil from idea through animal studies to clinical practice. For each proposed nanoagent, this step-wise approach will include in vivo: 1) characterization and optimization of the parameters most relevant to our system (i.e. adjuvant dosing, thermal dosing, interval timing of therapies, and the timing of maximal effect) in relevant animal models (R3230 rat mammary adenocarcinoma, and the MDR expressed and absent variants of M109 lung carcinoma, and Daoy medulloblastoma in mice); 2) correlation of endpoints of tumor destruction, drug uptake, and thermal dosimetry with the proposed relevant mechanisms; and 3) comparison of the two primary endpoints coagulation diameter and animal survival among the different proposed adjuvant nanotherapies alone and in combination (Aim 5). We additionally propose loading of clinically relevant imaging markers that will enable determination of correlation between spatial distribution at MR imaging of the relevant nanopreparations and resultant tumor destruction (Aim 4). Overall, this comprehensive approach will enable us to identify appropriate nanoagents for combination with RF ablation anticipated future clinical trials particularly for lung, liver, breast, and MDR tumors.